Franzén O, Ermel R, Cohain A, Akers NK, Di Narzo A, Talukdar HA, Foroughi-Asl H, Giambartolomei C, Fullard JF, Sukhavasi K, Köks S, Gan LM, Giannarelli C, Kovacic JC, Betsholtz C, Losic B, Michoel T, Hao K, Roussos P, Skogsberg J, Ruusalepp A, Schadt EE, Björkegren JL
Science 353 (6301) 827-830 [2016-08-19; online 2016-08-20]
Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention.
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